cgmp trends, data integrity and handling an fda inspection€¦ · fda draft guidance, “data...

CGMP Trends,

Data Integrity and

Handling an FDA Inspection

Mark SchwartzDirector

Hyman, Phelps & McNamara P.C.

September 6, 2018

1© Copyright 2018 by Hyman, Phelps & McNamara PC

TRENDS IN FDA INSPECTIONS

2© Copyright 2018 by Hyman, Phelps &

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Trends: What is FDA Focusing On?

Data integrity

• Electronic records systems are not Part 11 compliant

• Review of QA and QC data shows duplicate testing, and

“unofficial” testing

• Paper test reports and laboratory notebooks are not

controlled documents

• Lack of control over access to computerized systems

• Non-contemporaneous record-keeping

• Deletion, falsification, alteration, or other manipulation of

data

Supply chain

• API Repackers/Relabelers

• Contract Manufacturers

Rudimentary CGMP

• Release testing

• Cleaning, equipment maintenance, basic sanitation

• Cross-contamination risks

• Delay/Deny/Limit/Refuse Inspection

• Complaint handling, remediation, internal investigation

Sterility assurance

• Aseptic technique, environmental monitoring, design

• Defective smoke studies in aseptic processing areas

• Improper investigation of Environmental Monitoring results

and Personnel Monitoring results


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FDA Warning Letters Focus On Data Integrity

0

10

20

30

40

50

60

70

80

90

2011 2012 2013 2014 2015 2016 2017 2018

Nu

mb

er o

f W

arn

ing

Lett

ers Total CDER cGMP Warning

Letters (Worldwide)

CDER cGMP WarningLetters (Worldwide) CitingData Integrity Issues

Average % of Data Integrity Warning Letters 2011 – 2018: 43%

32%

38%

26%50%

50%

35%32%

Based on Warning Letters posted to FDA database as of August 27, 2018.

78%


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DATA INTEGRITY


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Data Integrity

Regulations and Guidance

• 21 CFR Part 11

Electronic Records; Electronic Signatures

• 21 CFR Part 210

CGMP in Manufacturing, Processing, Packing, Holding of Drugs; General

• 21 CFR Part 211

CGMP for Finished Pharmaceuticals

• Draft Guidance

“Data Integrity and Compliance with CGMP” (Apr. 2016)


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Data Integrity

• The completeness, consistency, and accuracy of data.

•ALCOA: Data should be attributable, legible, contemporaneously

recorded, original or a true copy, and accurate.

FDA Draft Guidance, “Data Integrity and Compliance with CGMP”

(April 2016)

7© Copyright 2018 by Hyman, Phelps & McNamara PC

Data Integrity BasicsBasic Principles

• Testing, analysis, and other activities must be documented at the time of performance.

• Backup data must be exact, complete, and secure from alteration or loss.

• True and complete copies (or other accurate reproductions) of original records must be maintained.

Computer Systems

• Have sufficient controls to prevent unauthorized access or data alteration.

• Maintain a record of any alterations made to data; the previous entry; who made the change, etc.

• Maintain a backup system if a breakdown in the primary system would result in permanent loss of records.

• Validate all CGMP-related computerized systems.

• Incidents that could affect the reliability of records or test results should be documented and investigated.

FDA Draft Guidance, “Data Integrity and Compliance with CGMP” (April 2016)


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Data Integrity Basics

• Use of CGMP Data

◦ Any data created to satisfy a CGMP requirement must be:

maintained for CGMP purposes (21 CFR § 211.180); and

evaluated by the quality unit as part of release criteria (21 CFR § 211.22).

◦ To exclude data from release criteria decision-making, there must be a valid, documented, scientific justification.

• Audit Trail Review

◦ Audit trails should be reviewed with each record and before final record approval.

◦ FDA recommends “routine scheduled audit trail review based on the complexity of the system and its intended use.”



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Data Integrity Basics:Paper vs. Electronic Records

• When data are generated to satisfy a CGMP requirement (whether electronic or paper), those data become a CGMP

record.

• Electronic records may be used as “true copies” of paper records, and paper printouts can satisfy retention

requirements in place of electronic records, if the paper printout is a complete copy of the original record.

• But, records (paper and electronic records alike) must be stored in a way that does not allow for manipulation, loss,

etc.



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Can an internal tip regarding a quality issue, such as potential data falsification, be handled

informally outside of the documented CGMP quality system?

NO

Suspected or known falsification or alteration of CGMP records must be fully

investigated within the quality system to determine:

• Effect of the event on patient safety, product quality, and data reliability;

• Root cause;

• Necessary CAPAs.


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Data Integrity Basics:Remediation

• Hire a reputable third-party auditor;

• Assess scope of the problem;

• Implement a CAPA globally.


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HANDLING AN FDA INSPECTION


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Before the Inspection

• Have an FDA Inspection SOP.

• Have third-parties conduct mock audits.

• Foster a culture of compliance.

• FDA may request documents “in advance of or in lieu of an inspection, within a reasonable timeframe, within

reasonable limits, and in a reasonable manner, and in either electronic or physical form.”

FDCA § 704(a)(4)

(FDASIA 2012)


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Arrival of the Investigators

The receptionist should:

• Ask the investigator(s) to sit in the lobby;

• Immediately contact management;

• If management is unavailable, ask investigator to either wait or return when management personnel are in the

facility;

• Refuse to sign anything, allow inspection of documents, or give out copies of documents.


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During the Inspection:Receiving the Investigator

The inspection team (escorts) should:

• Ask to see the investigator’s credentials;

• Ask to see the Form 482;

• Try to determine if any investigator is from FDA’s Office of Criminal Investigations;

• Tell the investigator that other employees are not authorized to speak for the company.


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During the Inspection:FDA’s Authority

FDA may inspect:

• facilities where drugs are manufactured or stored;

• equipment;

• finished and unfinished materials;

• containers;

• labeling; and

• records relating to CGMPs and pre-market approval applications.


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During the Inspection:FDA’s Authority

FDA may NOT

• Inspect:

o financial data;

o sales data (other than shipping data);

o pricing data;

o personnel data (except for qualifications of technical and professional personnel);

o research data (other than data relating to certain new drugs, devices, and other products subject to specific reporting and inspection requirements);

o internal audit reports; and

o internal reports and memos on factory inspections.FDCA § 704(a)

• Breach sterility or intervene with the production process.

Any request to inspect areas or data beyond the investigator’s authority must be made in writing.


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During the Inspection:FDA’s Authority:

Photography and Videotaping• FDCA does not indicate that photographs must be permitted.

• FDA Guidance states (at page 7): Conditions or practices effectively documented by photographs include “evidence of rodents or insect infestation; faulty construction or maintenance of equipment or facilities; product storage conditions; product labels and labeling; and, visible contamination of raw materials or finished products.”

• “Impeding or resisting photography by an FDA investigator may be considered a [unlawful] limitation if such photographs are determined . . . [t]o be necessary to effectively conduct that particular inspection.”

• Guidance does not require companies to allow videotaping

FDA Guidance, “Circumstances that Constitute Delaying, Denying, Limiting, or Refusing a Drug Inspection” (October 2014).


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During the Inspection:Do’s and Don’ts

Do:

• Record the purpose of the visit (e.g., routine inspection, complaint follow-up, pre-approval inspection, anticipation of enforcement or regulatory action);

• Escort the investigator(s) at all times;

• Funnel all requests for documentation, data, or product samples, etc. through the escort;

• Determine a schedule of events or (at a minimum) the areas to be covered and approximate time of day;

• Allow authorized employees to answer questions that are not inappropriate or leading;

• Tell the truth;

• Ask for clarification when necessary;

• Consult with counsel before signing any affidavit.


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During the Inspection:Do’s and Don’ts

Do not:

• Joke with the investigator;

•Volunteer information;

•Argue or make threatening remarks.


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During the Inspection:Availability of Employees

• FDCA does not mandate that employees must continue working or be made available when investigator arrives.

• However, FDA Guidance states (at page 6) that it is unlawful to “impede the investigator,” including when “[a] facility sends staff home for the day and tells the FDA investigator that the facility is not producing any product.”

• Guidance also states (at page 6) that a facility that “orders the discontinuation of all manufacturing for the duration of the FDA inspection without a reasonable explanation” also has “refused” to permit observation of the manufacturing process and thus prevented investigators “reasonable access” to areas “FDA is entitled to inspect.”

FDA Guidance, “Circumstances that Constitute Delaying, Denying, Limiting, or Refusing a Drug Inspection” (October 2014).


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During the Inspection:Problems and Corrective Actions

• Ask investigators to identify problems noted during the course of inspection so that they may be corrected as soon as

possible.

• When the investigator notes a problem

o Immediately inform the appropriate company employees;

o Try to correct before the inspection concludes.

• If the problem is corrected during the inspection:

o Tell the investigator(s) when the corrective action is taken;

o Ask the investigator(s) to either not mention the problem on the Form 483 or to indicate that the problem was corrected

during the inspection.


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During the Inspection:Close-Out Meeting

• Investigators will offer close-out meeting;

• Usually includes presentation of FDA Form 483;

• Take time to pose questions, seek clarification, and to the extent necessary, challenge the observations;

• Corrective actions can be noted on the 483;

• Do not make admissions, argue, or give a final response to the observations.


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After the Inspection

Do NOT commit to any corrective action unless employees are certain the commitment can be met.

Do follow up to assure that required actions are completed expediently.

Do prepare a 483 Response (i.e., responses to any Form 483 observations):

• Respond within 15 working days;

• Do not wait to receive the EIR;

• Be as thorough and detailed as possible;

• If FDA receives your response more than 15 days after the 483 is issued, the Agency may issue a Warning Letter

without reading your 483 Response.


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After the Inspection:Corrective Action

• If it’s not documented, it didn’t happen.

• Meetings with FDA can help, but usually are most constructive if they follow written submissions.

• Do not solicit guidance about something you should already know.

• Determine root causes; identify systemic issues; address issues globally.

• If you are unclear what corrective action is appropriate (and can’t find out), it is appropriate to ask FDA, but BEWARE.

• It can also be appropriate to ask if corrective action is sufficient, but, again, this can open the door to unhelpful suggestions/directives from FDA.

• When EIR is received, review carefully, and communicate any corrections.


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Questions?

27

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